US8541580B2 - Process for the preparation of pyrazinone thrombin inhibitor and its intermediates - Google Patents
Process for the preparation of pyrazinone thrombin inhibitor and its intermediates Download PDFInfo
- Publication number
- US8541580B2 US8541580B2 US12/938,297 US93829710A US8541580B2 US 8541580 B2 US8541580 B2 US 8541580B2 US 93829710 A US93829710 A US 93829710A US 8541580 B2 US8541580 B2 US 8541580B2
- Authority
- US
- United States
- Prior art keywords
- difluoro
- compound
- fluoropyridine
- pyridyl
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- AATHXZYXWMKUFC-UHFFFAOYSA-N O=C(CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl)NCC1=C(F)C=CC=N1 Chemical compound O=C(CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl)NCC1=C(F)C=CC=N1 AATHXZYXWMKUFC-UHFFFAOYSA-N 0.000 description 8
- 0 *B=S.*B=S.BrC1=NC=CC=C1.CCC1=NC=CC=C1F.CCOC(=O)CN1C=CN=C(Cl)C1=O.CCOC(=O)CN1C=CN=C(NCC(F)(F)C2=CC=CC=N2)C1=O.CCOC(=O)CN1C=CN=C(O)C1=O.FC1=CC=CN=C1.I.NCC(F)(F)C1=NC=CC=C1.NCC(F)(F)C1=NC=CC=C1.NCC1=NC=CC=C1F.OCC(F)(F)C1=NC=CC=C1.ON1=CC(F)=CC=C1 Chemical compound *B=S.*B=S.BrC1=NC=CC=C1.CCC1=NC=CC=C1F.CCOC(=O)CN1C=CN=C(Cl)C1=O.CCOC(=O)CN1C=CN=C(NCC(F)(F)C2=CC=CC=N2)C1=O.CCOC(=O)CN1C=CN=C(O)C1=O.FC1=CC=CN=C1.I.NCC(F)(F)C1=NC=CC=C1.NCC(F)(F)C1=NC=CC=C1.NCC1=NC=CC=C1F.OCC(F)(F)C1=NC=CC=C1.ON1=CC(F)=CC=C1 0.000 description 7
- VZFPSCNTFBJZHB-UHFFFAOYSA-N N#CC1=NC=CC=C1F Chemical compound N#CC1=NC=CC=C1F VZFPSCNTFBJZHB-UHFFFAOYSA-N 0.000 description 2
- QLRSPKRGYAGOEC-UHFFFAOYSA-N NCC1=NC=CC=C1F Chemical compound NCC1=NC=CC=C1F QLRSPKRGYAGOEC-UHFFFAOYSA-N 0.000 description 2
- QJZJZURTLSZERM-UHFFFAOYSA-M B.C.CC.CCOC(=O)CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl.CCOC(=O)CN1C=CN=C(Br)C1=O.CCOC(=O)CN1C=CN=C(NCC(F)(F)C2=NC=CC=C2)C1=O.CO.I.NCC(F)(F)C1=NC=CC=C1.NCC1=C(F)C=CC=N1.O=C(CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl)NCC1=C(F)C=CC=N1.O=C(O)CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl.O[K] Chemical compound B.C.CC.CCOC(=O)CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl.CCOC(=O)CN1C=CN=C(Br)C1=O.CCOC(=O)CN1C=CN=C(NCC(F)(F)C2=NC=CC=C2)C1=O.CO.I.NCC(F)(F)C1=NC=CC=C1.NCC1=C(F)C=CC=N1.O=C(CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl)NCC1=C(F)C=CC=N1.O=C(O)CN1C(=O)C(NCC(F)(F)C2=NC=CC=C2)=NC=C1Cl.O[K] QJZJZURTLSZERM-UHFFFAOYSA-M 0.000 description 1
- LYGZWKYQIZKXFC-UHFFFAOYSA-N CC1=CC=C(S(=O)(=O)OCC(F)(F)C2=CC=CC=N2)C=C1 Chemical compound CC1=CC=C(S(=O)(=O)OCC(F)(F)C2=CC=CC=N2)C=C1 LYGZWKYQIZKXFC-UHFFFAOYSA-N 0.000 description 1
- AHLZMMPDDACOQX-UHFFFAOYSA-N CCOC(=O)C(F)(F)C1=CC=CC=N1 Chemical compound CCOC(=O)C(F)(F)C1=CC=CC=N1 AHLZMMPDDACOQX-UHFFFAOYSA-N 0.000 description 1
- DCGSCXFLEBPBRU-UHFFFAOYSA-N CCOC(=O)CN1C(=O)C(NCC(F)(F)C2=CC=CC=N2)=NC=C1Cl Chemical compound CCOC(=O)CN1C(=O)C(NCC(F)(F)C2=CC=CC=N2)=NC=C1Cl DCGSCXFLEBPBRU-UHFFFAOYSA-N 0.000 description 1
- UJOPCSBFHKAXFB-UHFFFAOYSA-N NC(=O)C1=NC=CC=C1F Chemical compound NC(=O)C1=NC=CC=C1F UJOPCSBFHKAXFB-UHFFFAOYSA-N 0.000 description 1
- RTZZBUQTHNQTSR-UHFFFAOYSA-N OCC(F)(F)C1=CC=CC=N1 Chemical compound OCC(F)(F)C1=CC=CC=N1 RTZZBUQTHNQTSR-UHFFFAOYSA-N 0.000 description 1
- POYLONJDIWUFHZ-UHFFFAOYSA-M [Li]OC(=O)C1=NC=CC=C1F Chemical compound [Li]OC(=O)C1=NC=CC=C1F POYLONJDIWUFHZ-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
Definitions
- Described herein is an improved process for the preparation of 3-fluoro-2-pyridyl methyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide of compound of formula (I).
- the improvement comprises the preparation of intermediates namely, 2-aminomethyl-3-fluoropyridine or its salt (K1) and 2,2-difluoro-2-(2-pyridyl)ethylamine or its salt (K2).
- the present invention relates to a simple, commercially viable and industrially scalable process for the preparation of compound of the formula (I) and its intermediates, which involves the use of cost effective raw materials, simple isolation of the product, purification and work-up.
- the present invention also relates to a simple and industrially scalable process for the preparation of compound of formula (I) and its intermediates, which avoids chromatographic purification techniques.
- the present invention provides an improved process for the preparation of compound of the formula (I).
- the invention comprises processes for making key intermediates namely, 2-aminomethyl-3-fluoropyridine as a hydrochloride salt (K1) and 2,2-difluoro-2-(2-pyridyl)ethylamine as a benzenesulfonic acid salt (K2).
- the intermediates (K1) and (K2) are used in the preparation of compound of formula (I), thrombin inhibitor.
- a process for the preparation of 2-aminomethyl-3-fluoropyridine as a hydrochloride salt (K1) is provided.
- a process for preparing 2-aminomethyl-3-fluoropyridine.2HCl (K1) comprises reduction of 3-fluoropyridine-2-carbonitrile of a compound of formula (D) with the reducing agent H 2 /Raney Ni in the presence of acetic acid or trifluoroacetic acid.
- the reported processes use expensive H 2 /Pd/C that is replaced with cost-effective Raney Nickel.
- the synthetic scheme for the preparation of 2-aminomethyl-3-fluoropyridine.2HCl is depicted in Scheme 1 as follows.
- a process for the preparation of 2,2-difluoro-2-(2-pyridyl)ethylamine as a benzenesulfonic acid (BSA) salt (K2) is provided (Scheme 2).
- the improved process utilizes p-toluenesulfonyl chloride (pTsCl or Tosyl chloride) in the preparation of a tosylate or mesylate (J) from the corresponding difluoro alcohol (H).
- Triflic anhydride ((F 3 CSO 2 ) 2 O) was used previously in place of low cost pTsCl or MSCl.
- a process for purifying 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, a compound of formula (I), using organic solvents including but not limited to ketones, alcohols, esters, ethers, hydrocarbons, halogenated solvents, and the like or a mixture thereof is provided.
- Ketones include, but are not limited to, acetone, butanone and the like.
- Alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, t-butanol, hexanol, isoamyl alcohol and the like.
- Esters include, but are not limited to, ethyl acetate, methyl acetate, isopropyl acetate and the like.
- Ethers include, but are not limited to, diisopropyl ether (IPE), methyl t-butyl ether (MTBE) and the like.
- Hydrocarbons include, but are not limited to, hexane, heptane, cyclohexane, decalin, pentane and the like.
- Halogenated solvents include, but not limited to, dichloromethane (MDC), 1,2-dichloroethane and the like or mixture thereof, preferably acetone, isopropyl alcohol or mixtures thereof.
- salts used herein includes inorganic acids such as hydrochloride (hydrochloric), hydrobromide (hydrobromic), sulfuric, sulfamic, phosphoric, nitric and the like, or quaternary ammonium salts, which are formed, e.g., from inorganic or organic acids or bases.
- inorganic acids such as hydrochloride (hydrochloric), hydrobromide (hydrobromic), sulfuric, sulfamic, phosphoric, nitric and the like, or quaternary ammonium salts, which are formed, e.g., from inorganic or organic acids or bases.
- acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulphonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, toluenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
- Solvates are addition complexes in which a compound is combined with a solvent in some fixed proportion.
- Solvents include, but are not limited to water, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol, t-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene, toluene, xylene, ethylene glycol, dichloromethane, 1,2-dichloroethane, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, pyridine, dioxane, diethyl ether and the like. Hydrates are solvates in which the solvent is water. It is to be understood that the definition of the compounds or intermediates of the present invention encompasses all possible hydrates and solvates, in any proportion.
- thromboin inhibition is used for anticoagulant therapy in individuals having thrombotic conditions, and whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Therefore, thrombin inhibitors are added to any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited.
- the present invention provides an improved process for the preparation of compound of formula (I); an improved process for the preparation of key intermediates of the compound of formula (I); and/or a pharmaceutical composition comprising the compound; and/or a compound for inhibiting thrombin; and/or an improved method for inhibiting thrombin in blood.
- Step-1 Lithium 3-fluoropyridine-2-carboxylate (B)
- the RM was cooled to ⁇ 75° C., then 10 g of 3-fluoropyridine (in 10 mL of MTBE) was added dropwise while maintaining the temperature in the range of ⁇ 75° C. to ⁇ 70° C.
- the RM was stirred at the same temperature for 4 hours.
- 100 mL of tetrahydrofuran (THF) was taken and cooled to ⁇ 70° C. followed by bubbling of CO 2 gas for 1 hour.
- lithiated 3-fluoropyridine solution mixture of 3-fluoropyridine+n-BuLi+TMEDA in MTBE was added dropwise using cannula maintaining the reaction temperature below ⁇ 70° C. ( ⁇ 70° C.
- Step-4 Preparation of 2,2-Difluoro-2-pyridin-2-ylethanamine benzenesulfonate salt (K2)
- the crude mass obtained was dissolved with 10 mL of MDC, and to this 4.5 g benzene sulphonic acid (BSA) dissolved in 30 mL isopropyl acetate (IPAc) was added dropwise over a period of 30 minutes with stirring at RT.
- the RM was stirred for 30 minutes at RT.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
-
- (a) reducing nitrile compound of formula (D) with a reducing agent such as H2/Raney Nickel optionally in presence of acid selected from acetic acid, trifluoroacetic acid to amine compound of formula (K1) and
- (b) isolating 2-aminomethyl-3-fluoropyridine preferably as its hydrochloride salt by treatment with either alcoholic HCl such as IPA.HCl or purging dry HCl in a suitable organic solvent selected from toluene, IPA, MeOH, EtOH and the like or mixture thereof.
-
- (i) converting difluoro ethanol compound of formula (H) to tosylate compound of formula (J) using tosyl chloride or mesyl chloride and
- (ii) treating mesylate or tosylate compound of formula (J) with ammonia to yield difluoroamine compound of formula (K2).
-
- (A) reacting 2,2-difluoro-2-(2-pyridyl)ethylamine or its salt (K2) with 3-chloropyrazin(1H)-2-one-1-acetate (K3) to form ethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-pyrazin(1H)-2-one-1-acetate (K);
- (B) chlorinating the compound of formula (K) and further reacting with 2-aminomethyl-3-fluoropyridine or its salt (K1) to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, the compound of formula (I); and
- (C) optional purification of compound of formula (I).
in which 2,2-difluoro-2-(2-pyridyl)ethylamine or its salt (K2) is reacted with ethyl 3-chloropyrazin(1H)-2-one-1-acetate (K3) to form ethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-pyrazin(1H)-2-one-1-acetate (K), chlorinated, which is further reacted with 2-aminomethyl-3-fluoropyridine or its salt (K1) to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, the compound of formula (I), the improvement comprising:
Claims (13)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2663/CHE/2009 | 2009-11-03 | ||
IN2663CH2009 | 2009-11-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
US20110105753A1 US20110105753A1 (en) | 2011-05-05 |
US8541580B2 true US8541580B2 (en) | 2013-09-24 |
Family
ID=43926105
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/938,297 Expired - Fee Related US8541580B2 (en) | 2009-11-03 | 2010-11-02 | Process for the preparation of pyrazinone thrombin inhibitor and its intermediates |
Country Status (10)
Country | Link |
---|---|
US (1) | US8541580B2 (en) |
EP (1) | EP2496087A4 (en) |
JP (1) | JP2013510159A (en) |
KR (1) | KR20120106727A (en) |
CN (1) | CN102711481A (en) |
AU (1) | AU2010315338A1 (en) |
CA (1) | CA2778922A1 (en) |
MX (1) | MX2012005165A (en) |
RU (1) | RU2012118499A (en) |
WO (1) | WO2011056806A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2012336036A1 (en) | 2011-11-07 | 2014-06-19 | Diakron Pharmaceuticals Inc. | An extended release formulation of a direct thrombin inhibitor |
WO2017072039A1 (en) | 2015-10-26 | 2017-05-04 | Bayer Cropscience Aktiengesellschaft | Condensed bicyclic heterocycle derivatives as pest control agents |
WO2020173860A1 (en) | 2019-02-26 | 2020-09-03 | Bayer Aktiengesellschaft | Fused bicyclic heterocycle derivatives as pesticides |
AU2020228119A1 (en) | 2019-02-26 | 2021-09-16 | Bayer Aktiengesellschaft | Condensed bicyclic heterocyclic derivatives as pest control agents |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6147078A (en) | 1998-05-19 | 2000-11-14 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
WO2002046160A2 (en) | 2000-12-06 | 2002-06-13 | Merck & Co., Inc. | Process for making a thrombin inhibitor |
US6455532B1 (en) | 1999-06-04 | 2002-09-24 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
EP1422221A1 (en) | 2002-11-20 | 2004-05-26 | Bayer CropScience SA | Novel process for the preparation of 2-aminomethylpyridine derivative |
-
2010
- 2010-11-02 CA CA2778922A patent/CA2778922A1/en not_active Abandoned
- 2010-11-02 CN CN2010800499062A patent/CN102711481A/en active Pending
- 2010-11-02 RU RU2012118499/04A patent/RU2012118499A/en not_active Application Discontinuation
- 2010-11-02 WO PCT/US2010/055176 patent/WO2011056806A1/en active Application Filing
- 2010-11-02 KR KR1020127010789A patent/KR20120106727A/en not_active Application Discontinuation
- 2010-11-02 AU AU2010315338A patent/AU2010315338A1/en not_active Abandoned
- 2010-11-02 US US12/938,297 patent/US8541580B2/en not_active Expired - Fee Related
- 2010-11-02 EP EP10828989.3A patent/EP2496087A4/en not_active Withdrawn
- 2010-11-02 JP JP2012537955A patent/JP2013510159A/en active Pending
- 2010-11-02 MX MX2012005165A patent/MX2012005165A/en active IP Right Grant
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6147078A (en) | 1998-05-19 | 2000-11-14 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
US6455532B1 (en) | 1999-06-04 | 2002-09-24 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
WO2002046160A2 (en) | 2000-12-06 | 2002-06-13 | Merck & Co., Inc. | Process for making a thrombin inhibitor |
EP1422221A1 (en) | 2002-11-20 | 2004-05-26 | Bayer CropScience SA | Novel process for the preparation of 2-aminomethylpyridine derivative |
US7456290B2 (en) | 2002-11-20 | 2008-11-25 | Bayer Cropscience S.A. | Process for the preparation of 2-aminomethylpyridine derivative |
Non-Patent Citations (6)
Title |
---|
Ashwood et al., "Development of a Scaleable Synthesis of a 3-Aminopyrazinone Acetamide Thrombin Inhibitor", Organic Proc. Res. Dev. 8(2):192-200, 2004. |
Burgey et al., "Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines," J. Med. Chem., 2003, vol. 46, pp. 461-473. |
Friedrich et al., "Titanium and Zirconium Complexes Containing a Novel Dianionic Trifunctional Amido Ligand," Chem. Ber./Recueil 1997, vol. 130, pp. 1751-1759. |
International Search Report and Written Opinion issued in corresponding PCT Application No. PCT/US10/55176, mailed Jan. 18, 2011. |
Supplementary Search Report in corresponding European Patent Application No. 10828989.3 dated May 23, 2013. |
Wade, Jr., L.G., "Reactions of Alcohols," Organic Chemistry, 5th Edition, Chapter 11, PowerPoint Presentation, Dallas County Community College District, Slides 12-15 (2003); faculty.smu.edu/ebiehl/organic/Wade11.ppt. |
Also Published As
Publication number | Publication date |
---|---|
CN102711481A (en) | 2012-10-03 |
AU2010315338A1 (en) | 2012-05-24 |
US20110105753A1 (en) | 2011-05-05 |
EP2496087A1 (en) | 2012-09-12 |
KR20120106727A (en) | 2012-09-26 |
CA2778922A1 (en) | 2011-05-12 |
JP2013510159A (en) | 2013-03-21 |
WO2011056806A1 (en) | 2011-05-12 |
EP2496087A4 (en) | 2013-06-19 |
RU2012118499A (en) | 2013-12-10 |
MX2012005165A (en) | 2012-08-08 |
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